Neurotransmitter serotonin or 5-Hydroxytryptamine (5-HT) is abundantly distributed in the central nervous system, including hippocampus and frontal cortex. 5-HT receptors are a family of G-protein coupled receptors, characterized with 7-transmembrane helices and presently have fourteen known receptor subtypes, some of which exist as multiple splice variants [D. L. Murphy, A. M. Andrews, C. H. Wichems, Q. Li, M. Tohda and B. Greenberg, J. Clin. Psychiatry, 1998, 59 (suppl. 15), 4]. 5-HT influences a number of physiological functions and is implicated in a large number of central nervous system disorders, vascular diseases, neurodegenerative diseases and others (Childers, W. E., et. al., Ann. Rep. Med. Chem. 2005, 40, 17).
5-HT2B receptors are widely distributed in mammalian peripheral tissues including lung, heart, pancreas, spleen, prostate, liver, vascular and skeletal muscle, adipose tissue, intestine, ovary, uterus, testis, and in the central nervous system (CNS) including brain and cerebral cortex. 5-HT2B receptors are expressed in pulmonary endothelial and smooth muscle cells in humans. 5-HT2B receptors stimulate calcium release in human endothelial cells from the pulmonary artery (Esteve, J. M., Launay, J. M., Kellerman, O., Maroteaux, L., Functions of serotonin in hypoxic pulmonary vascular remodeling. Cell Biochem. Biophys, 2007, 47, 33-44). The receptor was characterized in the rat gastric (fundus) smooth muscle cells initially as the receptor responsible for mediating serotonin-induced contraction in this tissue.
The serotonin receptor 5-HT2B regulates cell-cycle progression via receptor tyrosine kinases pathways. It has been reported that activation of the 5-HT2B receptor by the neurotransmitter 5-HT leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and kinases (cyclin D1/cdk4 and cyclin E/cdk2) by induction of cyclin D1 and cyclin E protein. While Cyclin D1 induction is controlled by mitogen-activated protein kinase (MAPK), cyclin E induction is not, indicating an independent regulation of both these cyclins in the 5-HT2B receptor mitogenesis. It has also been shown that platelet-derived growth factor receptor (PDGFR) kinase activity is critical for 5-HT2B-triggered MAPK/cyclin D, but not cyclin E, signaling pathways by using a specific PDGFR inhibitor. Activation of 5-HT2B receptor increases activity of the Src kinase family, c-Src, the crucial protein between the Gq-protein coupled receptor 5-HT2B and the cell cycle regulators. Inhibition or depletion of c-Src activity eliminates the 5-HT-induced PDGFR tyrosine kinase phosphorylation, MAPK activation, cyclic D1 and cyclin E expression levels and thymidine incorporation (Nebigil, C. G; Launay, J-M; Hickel, P.; Tournois, C.; Maroteaux. et. al. Proc. Natl. Acad. Sci. (PNAS), USA., 2000, 97, 2591-2596).
Ras protein is involved in the signal transduction by the 5-HT2B receptor. Activation of the 5-HT2B receptor stimulates ras-mitogen activated protein kinase (ERL/MAPK) cascade. The 5-HT2 receptors stimulate the phospholipase C second messenger pathway via the α subunit of the Gq GTP-binding protein. Agonist stimulation of the 5-HT2B receptor (stably expressed in the mouse fibroblast cell line LMTK) causes rapid and transient activation of the proto-oncogene product p21ras as measured by an increase in GTP-bound Ras in response to 5-HT. Moreover, 5-HT2B receptor stimulation activates p42mapk/p44mapk (ERK2/ERK1) mitogen-activated protein kinases as assayed by phosphorylation of myelin basic protein. Furthermore antibodies against p21ras, Gαq, −β, or −γ2 subunits of the GTP-binding protein inhibit MAP kinase-dependent phosphorylation. The MAP kinase activation is correlated with 5-HT-stimulated cell division.
In addition to this mitogenic activity, transforming activity of 5-HT is mediated by the 5-HT2B receptor, since its expression in the LMTK cells is absolutely essential for foci formation and subsequently for these foci to form tumors in nude mice. Furthermore, expression of 5-HT2B receptors in spontaneous human and Mastomys natalensis carcinoid tumors has been detected. Similar to the 5-HT2B receptor transfected cells, the Mastomys tumor cells are also responsive to 5-HT with similar coupling to p21ras activation. In 5-HT2B receptor mitogenesis, c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK pathway.
Sorafenib (BAY 43-9006, Nexavar), a dual acting multiple kinase inhibitor of RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature has also shown unexpected binding affinity for three 5-HT receptor subtypes including 5-HT2B (Ki=56 nM), 5-HT2C (Ki=417 nM) and 5-HT2A (Ki=1959 nM), with highest binding affinity for the 5-HT2B receptor. Sorafenibnib has been approved as an anticancer drug as Nexavar by the USFDA for the treatment of renal cell carcinoma (primary kidney cancer) and hepatocellular carcinoma (advanced primary liver cancer). Regorafenib (BAY-73-4506), a fluoro analog of sorafenib, also a multi-kinase (VEGFR, PDGFR, FGFR, KIT, RET, and Raf), inhibitor for the treatment of various cancers including metastatic colorectal cancer.
5-HT2B receptor antagonists are potential therapeutic agents in the treatment, prevention or cure of certain, multiple or all forms of cancers including kidney, liver, colorectal, breast, colon, thyroid, prostate, blood, head, neck, multiple myeloma, solid tumors and others.
5-HT2B receptor is also a novel target for drug development for the treatment, prevention and cure of chronic liver diseases including liver cirrhosis and fibrosis. It has been shown that 5-HT2B receptor antagonist stimulates regeneration of healthy tissue and block fibrosis in chronic liver disease. Furthermore, a 5-HT2B antagonist attenuated fibrogenesis and improved liver function in disease models of pre-established and progressive fibrosis (Ebrahimkhani, et. al., Nature Medicine 2011, 17, 1668-1673).
Tissue homeostasis requires effective wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue can lead to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that control the balance of cell regeneration and fibrogenesis are not well established. It has been shown that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration which requires stimulation of 5-HT2B receptors on HSCs by serotonin. Agonism of 5-HT2B receptors activates expression of transforming growth factor β1 (TGF-β1) via signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. TGF-β1 is a potent suppressor of hepatocyte proliferation. Selective antagonism of 5-HT2B receptors enhanced hepatocyte growth in models of acute and chronic liver injury. Similar effects have been observed in 5-HT2B knockout mice or JunD knockout mice or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Thus pharmacological modulation of 5-HT2B receptor may be a safe and effective therapeutic intervention in the treatment, prevention and possibly a cure of chronic liver diseases including but not limited to liver cirrhosis and fibrosis.
Congenital heart failure, pulmonary arterial hypertension and myocardial infarction are major causes of disability and morbidity. The molecular mechanism of cardiac adaptation (hypertrophy) and maladaptation (apoptosis) underlying cardiac pathogenesis is not well understood to date. Several lines of evidence suggest that serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that regulates cardiovascular functions. It has been shown that inactivation of the Gq-coupled 5-HT2BR gene leads to partial embryonic lethality due to trabeculae defects. It has been demonstrated that newborn 5-HT2B receptor mutant mice exhibit cardiac dilation resulting from contractility deficits and structural deficits at the intercellular junctions between cardiomyocytes. Cultured cardiomyocytes and 5-HT2B receptor knockout mice were used as an animal model of dilated cardiomyopathy to identify the molecular mechanism of cardiac functions triggered by serotonin (Nebigil, C Etienne, N.; Messaddeq, N.; Maroteaux, L. Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5-HT2B receptor signaling, FASEB, 2003, 17, 1373-1375). These results identify 5-HT as a novel survival factor targeting mitochondria in cardiomyocytes. These findings suggest that the modulation of 5-HT2B receptor signaling have potential application in the prevention and treatment of acute myocardial infarction and congestive heart failure.
Serotonin (5-HT) affects the pulmonary vasculature associated with pulmonary arterial hypertension (PAH) by vasoconstriction, platelet aggregation, and pulmonary arterial smooth muscle cell proliferation. Serotonin receptors subtypes, 5-HT1B, 5-HT2A and 5-HT1B have shown evidence for playing a role in the pathology of PAH. 5-HT2B receptors are expressed in pulmonary endothelial and smooth muscle cells and stimulate calcium release in human endothelial cells from the pulmonary artery. It has been demonstrated that 5-HT2B receptors are involved in the development of PH by mediating chronic hypoxic responses in wild-type mice compared with the complete lack of PH and vascular remodeling in the 5-HT2B receptor (−/−) knockout mice in the chronic hypoxic mouse model of PH (Launey et. al., Function of the serotonin 5-Hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med. 2002, 8, 1129-1135).
5-HT2B receptor modulators (antagonists, partial agonists, inverse agonists and agonists) have the potential to be selective for diseased pulmonary trachea, thymus, thyroid, salivary gland vasculature (i.e., vessels affected by hypoxic conditions) compared to normal pulmonary and systemic vessels. Due to this selectivity, 5-HT2B modulators particularly 5-HT2B antagonists offer a possible therapeutic advantage over the available agents for the treatment of pulmonary arterial hypertension, pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD), right ventricular hypertrophy and related disease of the lung and vascular system.
Pulmonary hypertension (PH) is a progressive, debilitating and often fatal disease that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. PH is estimated to affect 100,000 people worldwide. Pulmonary arterial hypertension (PAH) is an increase in the pulmonary vascular resistance due to vasoconstriction and pulmonary vascular remodeling that result in elevated pulmonary arterial pressure. The cause of idiopathic PAH is unknown. PAH can be developed as a consequence of existing diseases such as chronic obstructive pulmonary disease (COPD) hypoxia, portal hypertension, or HIV infection. PAH is progressive and fatal. The median survival time without treatment in adult PAH patients is 2.8 years after diagnosis, and is only 10 months in children. Although survival rates have improved with new drugs, the prognosis is still poor and development of safer and more effective drugs is needed. Current treatments include systemically administered intravenous and subcutaneous prostacyclin analogs and orally active endothelin receptor antagonists, which mainly cause pulmonary arterial dilation to relieve symptoms. There is only one approved orally active agent for PH available for patients, a non-selective endothelin A and B receptor antagonist which requires liver toxicity monitoring.
The role of 5-HT2B in pulmonary hypertension was recognized by the observation that there may be a relationship between the PAH patients taking weight reducing agents such as dexfenfluramine, fenfluramine and aminorex which are 5-HT2B agonists; that the use of these agents may be contributing towards the elevation of pulmonary arterial hypertension (Kramer. M. S., and Lane, D. A. A minorex, dexfenfluramine, and primary pulmonary hypertension, J. Clin. Epidemiol. 1998, 51, 361-364). Both a minorex and fenfluramine elevates 5-HT levels by increasing the release of 5-HT from platelets and inhibiting the metabolism and the reuptake of 5-HT (Maclean, M. R., Pulmonary hypertension, anorexigens, and 5-HT: pharmacological synergism in action? Trends Pharmacology. Sci. 1999, 20, 490-495; Belohlavkova, S., Simok, J., Kokesova, A., Hnilickova, O., Hampl, V., Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and potassium channels. J. Appl. Physiol. 2001, 91, 755-761). Dexfenfluramine has binding affinity for 5-HT2 receptors and its major metabolite, N-de-ethylated dexfenfluramine is a potent agonist of the 5-HT2B receptor and thus is involved in the development of PAH.
A novel and potent 5-HT2B receptor antagonist has been shown to significantly reduce the elevation in pulmonary arterial pressure and right ventricular hypertrophy and also maintains cardiac function. Pulmonary vascular remodeling was also decreased in rats. A 5-HT2B antagonist was shown to prevent the severity of PAH in the rat model (Porvasnik, S. L., Germain, S., Embury, J., Ganon, K. S., Jacques, V., Murray, J., Byrne, B. J., Shacham, S., Al-Mousily, F., J. Pharmaco. Exp. Ther. 2010, 334, 364-372).
The 5-HT2B receptor has also been shown to play a key role in the regulation of neuroendocrine tumor cell proliferation and the modulation of the fibroblast component of the neoplastic microenvironment (Svejda, B., et. al. Cancer 2010, 116, 2902-12). Small intestinal neuroendocrine tumors (SI-NETs) are cancers originating from serotonin-producing enterochromaffin cells in the diffuse neuroendocrine system. The carcinoid syndrome reflects excessive serotonin release. Carcinoid syndrome symptomatology includes bronchoconstriction, flushing, diarrhea, and fibrosis in the local peritumoral tissue and at distant in the heart or lungs. 5-HT shows both mitogenic and fibrogenic effects in fibroblasts, smooth muscle cells, and endothelial cells. These effects are mediated via the G-protein coupled 5-HT receptors, which activate mitogenic pathways through the extracellular signal-regulated kinase (ERK) pathway and JNK activation. Other studies have reported that 5-HT modulates valvular subendocardial cell proliferation. The human heart valves express messenger ribonucleic acid (mRNA) for 5-HT agonists (fenfluramine, dexfenfluramine, pergolide, cabergoline, ergotamine) are associated with pulmonary fibrosis and valvular heart disease (Roth, B., Drugs and valvular heart disease. N. Engl. J. Med. 2007, 356, 6-9; Gustafsson, B, Hauso, O., Drozdov, I., Kidd, M., Modlin, I., Cacinoid heart disease. Int. J. Cardio. 2008, 129, 318-324). Significant evidence exists for involvement of 5-HT2B receptors in cellular pathways that culminate in fibrosis. It has been recognized that SI-NETs are often present with fibrosis in the peritumoral tissue, the adjacent mesentery and peritoneum as well as in the right side of the heart or lungs (Modlin, I., Moss, S., Chung, D., Jensen, R., Snyderwine, E., Priorities for improving the management of gastroentero-pancreatic neuroendocrine tumors. J. Natl. Cancer. Inst. 2008, 100, 1282).
The proliferative activity of 5-HT has been shown to be dependent on the expression of 5-HT2 receptor subtypes (Kidd, M., et. al. Inhibition of proliferation of small intestinal and bronchopulmonary neuroendocrine cell lines by using peptide analogs targeting receptors. Cancer. 2008, 112, 1404-1414). Similar proliferation effects have been observed in the 5-HT secreting prostate cancer cell line PC3 (Dizeyi, N., et. al. Expression of serotonin receptors 2B and 4 in human prostate cancer tissue and effects of their antagonists on prostate cancer cell lines. Eur. Urol. 2005, 47, 895-900), 5-HT2A receptor expressing breast cancer cell line MCF-7 (Sonier, B., et. al. The 5-HT2A serotoninergic receptor is expressed in the MCF-7 human breast cancer cell line and reveals a mitogenic effect of serotonin. Biochem. Biophys. Res. Commun. 2006, 343, 1053-1059), and in human choricarcinoma cell line JEG-3 and BeWO (Sonier, B., et. al. Expression of the 5-HT2A serotoninergic receptor in human placenta and choriocarcinoma cells: mitogenic implications of serotonin. Placenta. 2005, 26, 484-490).
During the investigation of signal transduction pathways involved in the antiproliferative effect of 5-HT2B receptor antagonist, by investigating phosphorylation of ERK, direct role of 5-HT2 receptor subtypes has been demonstrated in vascular and tracheal smooth muscle cell proliferation. The mechanism involves coupling of 5-HT2A receptors and the ERK pathway, while 5-HT2B receptors activate ERK through the RAS pathway (Nebigil, C. G., et. al. 5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tryrosine kinase pathways. Proc. Natl. Acad. Sci. USA. 2000, 97, 2591-2596); Hershenson, M. B., et. al. Histamine antagonizes serotonin and growth factor-induced mitogen-activated protein kinase activation in bovine tracheal smooth muscle cells. J. Biol. Chem. 1995, 270, 19908-19913); Banes, A., et. al., Mechanism of 5-hydroxytryptamine 2A receptor activation of the mitogen-activated protein kinase pathway in vascular smooth muscle. J. Pharmacol. Exp. Ther. 1999, 291, 1179-1187).
Fibrosis is an important key feature of small intestinal neuroendocrine tumor (SI-NETs) both in local peritumoral tissue and systemic (cardiac) sites. 5-HT is a well known inducer of fibrosis. The growth factors regulating fibrosis and proliferation in the tumor microenvironment and mechanisms are unclear. It has been shown that blocking 5-HT2B receptors on tumor cells inhibit SI-NET 5-HT release and in turn fibroblast activation in the tumor microenvironment. In the 5-HT2B expressing SI-NET cell line, KRJ-1, a 5-HT2B antagonist has been shown to inhibit proliferation and 5-HT secretion and decreased ERK1/2 phosphorylation and profibrotic growth factor synthesis and secretion (transforming growth factor beta-1 {TGFβ1}), connective tissue growth factor (CTGF) and fibroblast growth factor (FGF2). The 5-HT2B antagonist was also found to significantly decrease 5-HT release, TGFβ1, CTGF, and FGF2.
Blocking the 5-HT2B receptor with a 5-HT2B antagonist is an effective antiproliferative and antifibrotic strategy for SI-NETs because it inhibits tumor micronvironment fibroblasts as well as NET cells. Use of 5-HT2B receptor antagonists offers a possible effective therapeutic intervention to prevent tumor progression, fibrosis, and metastasis in the neuroendocrine neoplasia. It may also have therapeutic use in other fibrotic processes associated with neuroendocrine cell dysregulation such as Crohn's disease (Kidd, M., et. al. ILlbeta- and LPS-induced serotonin secretion is increased in EC cells derived from Crohn's disease, Neurogastroenterology and Motility, 2009; 21, 439-450).
The compounds of this invention represented by formula I are valuable in the prevention, treatment or cure of various disease conditions regulated directly or indirectly by the inhibition of 5-HT receptors (antagonist) or activation of the neurotransmitter serotonin 5-HT (partial or full agonists). These diseases include chronic liver diseases, liver cirrhosis, liver fibrosis, hepatocellular carcinoma, renal cell carcinoma, kidney cancer, brain cancer, breast cancer, blood cancer, colorectal cancer, lung cancer, liver cancer, ovarian cancer, pancreas cancer, prostate cancer, stomach cancer, testicular cancer, uterus cancer, intestinal cancer, skin cancer, and other forms of cancer, carcinoid tumors, tumor progression, metastasis and fibrosis in the neuroendocrine neoplasia, fibrotic processes associated with neuroendocrine cell dysregulation for example Crohn's disease, chronic kidney disease, Focal Segmental Glomerulosclerosis (FSGS), proteinuria, pulmonary arterial hypertension, pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD), right ventricular hypertrophy, pulmonary vascular remodeling, asthma, cystic fibrosis, hypertension, ischemic stroke, angina pectoris, congestive heart failure, acute myocardial infarction, arrhythmia, arterial fibrillation, neurodegenerative diseases, age-related macular degeneration, Alzheimer's disease, dementia, cognition impairment, memory decline, schizophrenia, dementia associated with Parkinson's and Huntington's disease, progressive supranuclear palsy (PSP), Parkinson disease, Huntington disease, Pick's disease and Jacob disease, gastrointestinal disorders including irritable bowel syndrome, gastroesophageal reflux disease, Crohn's disease, gastric emptying disorders, gastritis, emesis, nausea, vomiting, prokinesia, non-ulcer dyspepcia, urinary incontinence, eating disorders, bulimia, anorexia, obesity, constipation, and respiratory depression, stress disorders, post-traumatic stress disorder, acute stress disorder, delirium, anxiety, depression, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), bipolar depression, epilepsy, age-related macular degeneration, Down's syndrome, pain, migraine, panic disorders, social phobia, animal phobias, and obsessive compulsive disorders, substance-related disorders including dependence and abuse, intoxication, withdrawal, and delirium arising from the use of alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, hypnotics, and anxiolytics, demyelinating diseases including multiple sclerosis, ALS, peripheral neuropathy, postherpetic neurolegia, cereberal vascular disorders, acute or chronic cereberovascular damage, cerebral infarction, subarachanoid hemorrhage, and cerebral edema, bronchoconstriction, vasodilation, smooth muscle contraction, brain disorders, vascular disorders, blood flow disorders as a result of vasodilation and vasospastic diseases such as angina, vascular headache, Reynaud's disease, pulmonary hypertension, systemic hypertension, scleroderma, ischemia, sexual dysfunction, erectile dysfunction, cardiovascular system regulation, prophylaxis and treatment of cerebral infarct, stroke, cerebral ischemia; metabolic diseases such as obesity, diabetes, as well as the treatment of diseases of the intestinal tract, stress-related somatic disorders, bladder function disorders such as cystitis, stress-related urinary incontinence, urinary incontinence post prostate cancer-surgery, reflex sympathetic dystrophy including shoulder/hand syndrome, bladder function disorders such as cystitis, sexual dysfunction, erectile dysfunction, and any nociception, pain or migraine associated with the above mentioned conditions as well as a disease state modulated directly or indirectly with 5-HT receptors or kinases pathways including Breakpoint Cluster Region (BCR)-Abelson Tyrosine Kinase (ABL), Epidermal Growth Factor Receptor (EGFR), Platelet-Derived Growth Factor (PDGF),Vascular Endothelial Growth Factor (VEGF), Human Epidermal Growth Factor (Her),Extracellular Signal-Regulated Kinase (ERK), Proto-oncogene Tyrosine Protein Kinase (Sarc), Mitogen Activated Protein (MAP) Kinase, proto-oncogene receptor tyrosine (Met), TYRO3 (Protein Tyrosine Kinase 3), Maternal Embryonic Leucine zipper Kinase (MELK), Mammalian Sterile zo-like Kinase 4 (MST4), Feline Sarcoma and Feline Sarcoma-relatede (FPS/FER)Tyrosine Kinase, Cancer Osaka Thyroid Kinase aka MAPK-38 (COT), Pyruvate Dehydrogenase Kinase Isoform-2 (PDK2), Receptor d´ Origine Nantais Kinase (RON), NAUK-2, Mixed-Lineage Protein Kinase 3 (MLK3), Protein Kinase N3 (PKN3), and other family members.
The compounds of the invention disclosed here may be useful in the treatment, prevention or cure of chronic liver disease, including but not limited to liver cirrhosis, and liver fibrosis.
The compounds of this invention may also be useful in the treatment, prevention or curing hepatocellular carcinoma, liver cancer or cancer metastasis in the liver.
The compounds of this invention may also be useful in the treating, preventing or curing various other forms of cancers regulated by various protein tyrosine kinases since the 5-HT second messenger intracellular signal transduction involves various protein tyrosine kinases cascade.
The compounds of this invention may have therapeutic use in treating, preventing or curing various forms of cancer including but not limited to kidney cancer, colorectal cancer, breast cancer, prostate cancer, ovarian cancer, lung cancer, skin cancer, head and neck cancer, solid tumors and non-small cell lung cancer, carcinoid tumors or teratocarcinoma.
The compounds of this invention may have therapeutic use in preventing treating or curing cognition or memory dysfunction due to Alzheimer's disease, progressive supranuclear palsy, PSP, (a form of frontotemporal demential (FTD), Parkinson disease, psychosis, Huntington disease, cognitive impairment (CMI), CMI associated with schizophrenia, post-tramatic syndrome, depression, stroke, stress, surgery, congestive heart failure and myocardial infarction.
The compounds of this invention may have therapeutic uses in treating, preventing and curing obesity and/or diabetes.
The compounds of this invention may have therapeutic uses in treating, preventing and curing chronic kidney disease.
These compounds may also have applications in the treatment of gastrointestinal disorders including irritable bowel syndrome, gastroesophageal reflux disease, Crohn's disease, gastric emptying disorders, gastritis, emesis, nausea, vomiting, prokinesia, non-ulcer dyspepcia, urinary incontinence, eating disorders, bulimia, anorexia, obesity, constipation, constipation, and respiratory depression, stress disorders, post-traumatic stress disorder, acute stress disorder, delirium, anxiety, general anxiety disorders, depression, major depressive disorder, biopolar depression, attention deficit hyperactivity disorder (ADHD), psychosis, epilepsy, age-related macular degeneration, Down's syndrome, pain, migraine, panic disorders, social phobia, animal phobias, and obsessive compulsive disorders.
The compounds of formula I may also be valuable in substance-related disorders including dependence and abuse, intoxication, withdrawal, and delirium arising from the use of alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, hypnotics, and anxiolytics.
These compounds of formula I may also be useful for the prevention and treatment of demyelinating diseases including multiple sclerosis, ALS, peripheral neuropathy, post herpetic neuralgia, cerebral vascular disorders, acute or chronic cerebrovascular damage, cerebral infarction, subarachnoid hemorrhage, and cerebral edema.
In addition, compounds of the invention may be used for the treatment of bronchoconstriction, vasodilation, smooth muscle contraction, brain disorders, vascular disorders, blood flow disorders as a result of vasodilation and vasospastic diseases such as angina, vascular headache, Reynaud's disease, pulmonary hypertension, and systemic hypertension; neuropathological diseases such as Alzheimer's diseases, Parkinson's disease, Huntington's disease; cardiovascular system regulation, prophylaxis and treatment of cerebral infarct, stroke, cerebral ischemia; as well as the treatment of diseases of the intestinal tract.
The compounds of the present invention may also be useful in the treatment of stress-related somatic disorders, bladder function disorders such as cystitis, stress-related urinary incontinence, urinary incontinence post prostate cancer-surgery, reflex sympathetic dystrophy including shoulder/hand syndrome, bladder function disorders such as cystitis, and any nociception, pain or migraine associated with the above mentioned conditions.
The compounds of this invention may be useful in all diseases mentioned above when administered orally, intravenously, subcutaneously, topically, or inhalation, via nasal route, or as a suppository for rectal administration, or as a transdermal patch.
The compounds of the present invention may be administered for treating or preventing or curing a disease, as a single therapeutic agent or in combination with other available medicines known to treat diseases mentioned above by another mechanism-of-action to increase efficacy and/or safety and/or to lower dose level to minimize or eliminate adverse side effects associated with one or more therapeutic agents.